Process of making vitamin a



Patented Feb. 1a, 1945 2,369,156

UNITED STATES PATENT OFFICE PROCESS OF MAKING VITAMIN A Nicholas A. Milan, Belmont, Mum, asaignor to Research Corporation, New York, N. 1., a corporation of New York No Drawing. Application Anmt 22, 1940.

a Serial No. 853,775

2 Claims. (01. 280-617) The general object or the present invention is to provide a novel process tor the synthetic H H I 8 production of vitamin A and a number of related .o c oc,n, intermediate products. I K I The accepted chemical structure of vitamin A g is represented by the formula:

BIC on: on which reacts with the sodium ethylate yielding I OH: H 1 n n n a D Im 11 H m In the second step compound II is saponifled l with alcoholic potash and the resultin: slycidic acid, compound III, Equation B, is sepal rated and decarboxylated by distillation to produce 1-[2,6',6'-trimethyl cyclohexen-i-yll-3- It readily may be seen that vitamin A, as well methyl but-3114-514, command v Equation q as other antixerophthalmic carotenoids (antixerophthalmic provitamins) are related to p-ionone Emmi B which is a well known substance used as an 1111- cm cal portant ingredient in the synthesis of perfumes. xon H H & n

The first step in my process consists in the p n m B condensation of p-ionone with ethyl chloro- I o acetate (see Equation A) in the presence of solid anhydrous sodium ethylate, using anhydrous toluene or benzene as solvents, thereby producm in: compound 11, Equation A. a 3mm 6 3mm 4 cm 0m 0H1 Distillation n n n cm on oom ounam -0 n c=ol %-o=o+co.

80 H 1 ls-o olcmoooclm I Noocm, H CHI IV Monone compound rv may be prepared also by concg, g, densing, in an ethereal solution, p-ionone with K H H: H ethyl dichloroacetate (ClcCHCOOCaHs) in the H presence of dilute magnesium amalgam, yieldl ing compound Ha, Equation D, which latter may on. 01 be saponiiled with alcoholic potash and the resuiting saponiilcation product decarboxylated to product IV as in Equations 8 and C.

Equation D otehieii'nalkatmgi alcgholafis adVB3ZGgg8lY may; be on, on, ca. us con ensa on pro ey are ree from alcohols. p-iononmi- 19 6-000mm The reaction of Equation A is understood to Mil-Hg I H involve two reactions which proceed simultanecm ously or successively, i. e. the combination of the w p-ionone and the ethyl chloroacetate forming the compound Here it will be seen that compound Ila is identical with the intermediate product oi Equation A and when this product no is subjected to saponiflcation with alcoholic KOH as in Equation B it is simultaneously or successively converted into compound II and compound III.

In the third step, compound IV is condensed with sodium or lithium acetylides in a mixture of anhydrous ether and liquid ammonia at temperatures between 55 and 'l0 0. After the reaction is over. the ammonia is removed and the product treated with a dilute solution of tartaric acid, aitho sh q eous solutions oi ammonium sulfate, ammonium chloride or other organic acids may alsobe used. The resulting compound V, Equation E, is extracted i'rom this mixture in an impure state and may be puriiied either by high vacuum distillation in an inert atmosphere or by preparing its phthalic acid ester by reacting the mixture with phthalic anhydride in pyridine solution. The phthalic acid ester is subsequently saponifled to obtain the pure acetylene carbinol, compound V.

Equation! on. on.

N 11114 n s gn n 010- -c- -cn inu umnnl H Compound V may be prepared also (see Equation-Fl by the interaction of the mono-Grignard of acetylene (1165611132) and th aldehyde compound IV.

Equation F ECECMgX Compound IV c --0 Compound V In the iourth step compound V may be dehydrated by distilling under hiah vacuum with small amounts of naphthalene sultonic acid or p-toluene sultonic acid yielding compound VII directly (see Equation 0) Equation G Compound V i Compound VII (see Equation 1) dehydrating catalysts Plln Compound V+ Pyridine Equation! CH: CH:

KOK E H g H C=C IauC-CECH CmundVI s H CHI vn Inthei'lithsteptheGrianardcralkalimetal acetylide oi compound VII is slowly added methyl vinyl ketone whereby the product VIII is iormed (see Equation-1).

Equation J on. on.

CH: CH!

C I H:

H t CH:

VIII

Equation it Pd or active iron cm CH:

is a Compound VIII-l- In the seventh step, compound u: may be treated with acetic anhydride to iorm the acetic ester of vitamin A, compound XI, Equation L.

Equation L acetic anhydride Compound XI Compound IX+ (I66 Eq ation Better yields of the acetate are obtained when compound III is treated first with phosphorus tribromide in pyridine yielding compound II, Equation M, which latter is treated with potassium acetate yielding compound In, Equation N.

Equation M PBrs Compound!!! e p dine OH: H!

OH; CHs H K 6 H H H B H C=C -C-C=C O-CBsBI' H OH:

accuse Equation N potassium acetate Compound! heat on, on.

CH| CHI n n )2 n a n J, a n a H C=C- CC=C- C-g-O l H: n on.

The vitamin is finally prepared by saponifying compound XI, Equation 0, or by treating compound X with silver hydroxide (see Equation P).

Equation 0 Compound XI 0 Compound I alcoholic KOH 00-70 0. in N atmosphere Equation P on Compound X -0 Compound I in alcoholic solution up to 50 C.

In the preparation 0! compound XI, the tollcwing alternative route may be used: Methyl vinyl ketone is condensed with sodium or lithium acetylide in liquid ammonia to produce compound XII, Equation Q, which latter is then converted into the Grignard XIII, Equation'R, by interaction with ethyl magnesium bromide. The Grignard XIII is allowed to react in ether solution with the aldehyde IV followed by hydrolysis with tartaric acid or ammonium sulfate to produce compound XIV. Equation 8.

' Equation Q 11 on. HCECNe E n,c=c-c=o n,c=c- CECH in liquid NE:

Equation R CB: ZCaHIMgBr n J: OompoundXlI n,c=c- CECMgBr MgBr xzn

Equation S followed by Com arv Com lllld. xru Mam-121mb m m 'tartaric acid or (NHdrSOi on. em AH H g H 1 H a n c=c- -c-c c- -c.-=c n L} in s. H CH:

XIV

Compound XIV is then partially reduced to compound XV using the catalysts and conditions described above (see Equation T).

Equation T I Ommnd xlv+ Pd on CaCO:

or BaSOi H: CH;

1 CHI 2: n A n n n J; n n c=cc-c=c- -c=crn H in in An alternative method used to prepare compoundxfvconsistelntheinteractionoithe Grignard of V with methyl vinyl ketone (see Equation U).

' Equation v Oriana-rd oi V on on Equation W PEI: -r Pyridine at 0 C.

CH] CHI Equation Y xv1+ mm c a x -O om an alcohol Do A more detailed account oi the principal reactions is to be found in the following pages.

Pursssrron or GLYCID Esrln Comrormn II, FIRST Brae, Eqnarzorr A Twenty-four grams of metallic sodium is dissolved in about 300-400 cc. of absolute ethyl alcohol in a one liter filter flask fitted with a reflux condenser. It has been found preferable to add all oi? the sodium at once and after it has gone into solution, the alcohol is removed under reduced pressure at temperatures ranging between A white sodium ethylate results. This is added slowly to a vigorously stirred mixture of 192 grams of p-ionone, 122 grams ethyl chloroacetate and 110 cc. of anhydrous toluene (benzene may also be used) at 0. After all oi the sodium ethylate has been added, stirring is continued until the mixture becomes homogeneous and brownish in color then allowed to stand at room temperature for 7-10 hours. It is then heated on the water bath for 5 hours, cooled to room temperature and acidified with 25% acetic acid. The oil separating from this mixture is fractionated under reduced pressure and the fraction boiling at 152-155 (2-3 mm.) collected. A yield of about 80% of compound II is obtained.

Paarsasnou or Couromms III we IV, Sacono Sm, EQUATIONS B can 0 To obtain III, 107 g. of compound II is mixed with one equivalent (21.6 g.) of 10% alcoholic potash and the mixture heated on the water bath for about two hours. The alcohol is then removed under reduced pressure and the residue dissolved in the minimum amount of water and the aqueous mixture extracted a few times with ether to remove any unsaponltlable matter. The aqueous solution is then treated with 25% phosphoric acid and the oily layer which separates extracted with ether. The ether extract is then dried with anhydrous magnesium suliate, filtered and the ether removed under reduced pressure. The residue (compound III) is heated in an atmosphere of nitrogen and in the presence powdered glass to facilitate the removal of carbon dioxide and the aldehyde formed finally tractionated under reduced pressure and the traction boiling at Mil-145 mm.) collected. A yield of about 05-90% of compound IV is obtained. This has an a 1.5032 and forms a 2,4-dinltrophenylhydrazone; M. P. 155-157 having the correct combustion analysis.

This aldehyde (compound IV) has also been prepared by the alternative method (Equation D) described as part of the second step.

PREPARATION or Cosreomm V, THIRD Bree, Eons-non E To about 1 l. of liquid ammonia, in a B-necked flask equipped with a Hershberg stirrer and a dropping tunnel, was added 1 g. of hydrated ferric nitrate and 1 g. oi metallic sodium and the mixture stirred for 1 hour while the temperature was kept at 55 to 'l0. To this mixture was then added a trifle excess over half a moi of metallic sodium and the mixture stirred for half an hour longer. Dry acetylene was then passed through the mixture for several hours or until most or the blue color had assumed a gray-white color. To this mixture was then added, in the course of three hours. 46 g. oi compound IV in 200 cc. of anhydrous ether taking care that the temperature of the mixture never rises above 60 and that the stirring is very rapid. After all of the aldehyde has been added, the mixture is stirred for 24 hours longer, keeping the temperature between ---55 and -'I0. The ammonia is then allowed to evaporate and the brownish residue treated with excess cold aqueous solution or d-tartaric acid and the resulting mixture extracted with ether from which the acetylene carbinol. compound V, is isolated either by distillation under high vacuum mm.) or by preparing its acid phthalate ester in anhydrous pyridine and subsequently saponiiying this ester to obtain the pure acetylene carbinol. The phthaiic acid ester had the correct analysis and semi-microhydrogenation revealed the presence cl 4 double bonds. The acetylene carbinol also gives a heavy whitish-gray precipitate with ammonlacal alcoholic silver nitrate solution characteristic for acetylenes.

Compound V has also been prepared, in anhydrous ether solution, by the interaction of compound IV with the mono-Grignard of acetylene (HCECMgBr), (Equation F).

Parrsasrron or Courotmbs VI AND VII, Fotm'rn Srrr Eone'rrons H up I Five g. of compound V is dissolved in about 15 g. of anhydrous pyridine and the mixture cooled between 0 and 5" C. To this mixture is slowly added about 2.2 g. 01' phosphorus tribromide taking care that the temperature does not rise above 0. After half an hour of standing at 0, the mixture is warmed to about -70 for 15 minutes, then, without separating compound VI, the mixture is treated with the calculated amount plus 10% excess of 10% alcoholic potash. The mixture is heated on the water bath for half an hour, then poured in four times its volume oi water. Th aqueous mixture is then extracted several times with ether and the ethereal solution shaken a number oi times with a solution oi dtartaric acid to remove the pyridine. Finally, the ether solution is dried over anhydrous magnesium sulfate, filtered. and the ether removed. The residue is nearly pure compound VII, although for further purification one can distill it under a very high vacuum.

Compound VII may also be prepared by distiliing compound V under reduced pressure (10- 10- mm.) in the presence or small amounts, 1 to 5%, of p-toluene sulfonic acid or naphthalene suli'onic acid (Equation G).

Paanae'rrou or Comm VIII, Finn S'rxr Equation J Five g. 0! compound VII in 30 cc. of anhydrous ether is slowly added to an ethereal solution or the calculated amount 0! ethyl magnesium bromide and the mixture refluxed in an atmosphere or nitrogen for 5 to 10 hours. To this mixture is then slowly added at 0 with stirring about 2 g. of methyl vinyl ketone which is freshly distilled from small amounts of hydroquinone. The mixture is allowed to stand at room temperature overnight then poured on to a mixture of ice and ammonium sulfate. Ai'ter the Grlgnard mixture is completely hydrolyzed. the ethereal layer is separated and dried over anhydrous magnesium sulfate, filtered, and the ether removed under reduced pressure. The residue which is nearly pure compound VIII may now be used for the next step.

Puritan-ion or Couroorm 1x, Brx'rn Sm Eons-non K Compound VIII is dissolved in absolute alcohol and to the solution added about one-twentieth oi the weight 0! compound VIII 0! 1% palladium black deposited on solid powdered carbonate made in accordance with methods described in the literature. Barium sulfate may be advantageously used as the support 0! the catalyst. The calculated amount 01' hydrogen to saturate one of the bonds of the triple bond is then allowed to be absorbed by the system. The mixture is then filtered and the filtrate distilled under moderately reduced pressure. The residue is nearly pure compound IX.

The reduction oi. compound VIII to compound IX may also be accomplished under 50-75 atmospheres 0! hydrogen at not higher than C. and in the presence of an active iron catalyst prepared by leaching the aluminum from an ironaluminum alloy (Equation K).

PREPARATION or Courom XI, Sxvxn'rn Srrr Equsrrons M su N Although compound XI may be prepared by the treatment of compound IX with acetic anhydride (Equation L), better yields are obtained by dissolving compound IX in anhydrous pyridin'e, cooling to 0, and adding the calculated amount of phosphorus tribromide, Equation M, taking care that the temperature does not rise above 0. The mixture is then warmed to room temperature and kept there for two hours. The mixture is then dissolved in ether and the etheral solution extracted with a cold 25% solution 01' acetic acid to remove the pyridine and the phosphorous acid. After the ethereal solution is driedover anhydrous magnesium sulfate, and filtered, the ether is removed under reduced pressure and the residue compound X, Equation M, is dissolved in glacial acetic acid and treated, in an atmosphere oi nitrogen, with freshly fused potassium acetate, Equation N. The mixture is gently heated for about 2 hours to not higher than 100 C., then poured in cold water and extracted with ether. The ether- CH eal solution is separated, dried, and the ether re- H H on. H moved. The residue contains considerable amount H of compound XI from which vitamin A can be easily prepared by saponifying it in the usual 5 H CH8 manner with alcoholic potash (Equation 0). However, in may be used directly as a vitamin A substitute' and reacting the same with methyl vinyl ketone. I claim: 2. As a new product a compound of the formula 1. Process of producing a compound of the 10 formula OH; on. on; on,

H n H CH: H =c- =CCEC 7-C=CH:

n n n 1 11 i H C=C =CCE -C=CH: H

, I H 15 s -cm HYCHa i which comprises forming the Grignard of a compound of the formula. 20

NICHOLAS A. MILAS.

Certificate of Correction Patent No. 2,369,156. February 13, 1945. NICHOLAS A. MILAS It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 5, first column, line 14, claim 1, for that portion of the formula reading and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 26th day of June A. D. 1945.

[small] LESLIE FRAZER,

Acting Commissioner of Patents.

cold water and extracted with ether. The ether- CH eal solution is separated, dried, and the ether re- H H on. H moved. The residue contains considerable amount H of compound XI from which vitamin A can be easily prepared by saponifying it in the usual 5 H CH8 manner with alcoholic potash (Equation 0). However, in may be used directly as a vitamin A substitute' and reacting the same with methyl vinyl ketone. I claim: 2. As a new product a compound of the formula 1. Process of producing a compound of the 10 formula OH; on. on; on,

H n H CH: H =c- =CCEC 7-C=CH:

n n n 1 11 i H C=C =CCE -C=CH: H

, I H 15 s -cm HYCHa i which comprises forming the Grignard of a compound of the formula. 20

NICHOLAS A. MILAS.

Certificate of Correction Patent No. 2,369,156. February 13, 1945. NICHOLAS A. MILAS It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 5, first column, line 14, claim 1, for that portion of the formula reading and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 26th day of June A. D. 1945.

[small] LESLIE FRAZER,

Acting Commissioner of Patents. 

